See Article by Warraich et alOver 70% of Medicare beneficiaries who are hospitalized for heart failure (HF) die or are rehospitalized by 1 year after discharge.1 Most suffer progressive functional decline, dependency, and poor quality of life over time. Although such grim outcomes are commonly attributed to cardiac disease, noncardiovascular complexities are also detrimental.2 Older adults hospitalized for HF are particularly vulnerable to the adverse effects from muscle atrophy,3 disability, confusion, comorbidities, and other intricacies which undermine potential for recovery and survival. Whereas physical activity is recommended as part of the guidelines for recovery in patients hospitalized for HF,4 the majority of older HF patients remain sedentary, often challenged by their noncardiovascular conditions. REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) is a ground-breaking HF exercise trial5 that is designed to fill the gaps left by the HF-ACTION trial (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training).6 The primary focus of the REHAB-HF trial is the utility of exercise therapy after acute hospitalization among older adults. In their report of a subset of REHAB-HF enrollees, Warraich et al7 extend the value of REHAB-HF by delineating important characteristics of this population that constitute critical impediments to exercise interventions.HF-ACTION is widely promulgated as an endorsement of exercise therapy for HF, yet it is commonly criticized for inherent limitations.8 End points included reduced all-cause mortality and hospitalization and improved quality of life with aerobic exercise in a diverse population already receiving optimal medical therapy.6,9,10 Still, statistically significant benefits of the exercise intervention for mortality and rehospitalization were only detected after adjustment for baseline characteristics predictive of these clinical outcomes (cardiopulmonary exercise test duration, left ventricular ejection fraction, depression, atrial fibrillation).8 Such statistical tweaking is regarded by many as a limitation, but more fundamentally, HF-ACTION enrolled only patients with EF ≤35% and excluded patients hospitalized in the past 6 weeks. Such restrictions overlook the potential utility of exercise in the many HF patients with preserved EF (which is particularly prevalent in older adults), and during the critical posthospitalization period when functional decline and rehospitalization are most likely to occur.11 An even more prominent criticism of HF-ACTION was the remarkably poor adherence it achieved with its exercise intervention despite considerable prompting and support. Patients attended on average only 1.8 of the prescribed 3 sessions/week. With the benefit of hindsight, it is notable that HF-ACTION failed to consider common noncardiovascular impediments to adherence such as multimorbidity, frailty, and cognitive impairment. Furthermore, the absence of strength, balance, or mobility training in HF-ACTION may have further exacerbated poor adherence, by omitting critical aspects of conditioning that address the idiosyncratic needs in this population (ie, they were too weak for the purely aerobic HF-ACTION intervention); this ultimately may have reduced the potential to successfully execute the protocol.The REHAB-HF trial is addressing these shortcomings with a physical therapy, site-based intervention designed to improve the strength, balance, endurance, and mobility of older adults hospitalized for HF, regardless of ejection fraction.5 The REHAB-HF trial is enrolling patients ≥60 years old who are hospitalized for HF and are expected to be discharged home. The intervention begins during hospitalization and continues after discharge 3 days per week for 12 weeks. The baseline characteristics of the first 202 (out of 360) patients enrolled in the REHAB-HF trial are reported in this issue of Circulation: Heart Failure. The report highlights the large number of comorbid illnesses and high prevalence of depression, cognitive impairment, debilitating HF symptoms, and physical frailty. Although the REHAB-HF intervention focuses primarily on exercise therapy to improve physical deficits, this report expands the value of the trial by recognizing the diverse dimensions that impact exercise feasibility and sustainability.12 Such perspectives can not only be used to shape exercise prescription, but to ultimately inform exercise and wellness strategies that can be further studied as part of multifaceted cardiac rehabilitation programs.Comorbid conditions are associated with reduced exercise adherence among patients with HF.12 REHAB-HF participants have an average of ≥5 comorbid illnesses. Comorbid illnesses that limit mobility—such as arthritis or neurological conditions—may prevent patients from participating in exercise or rehabilitation. Furthermore, comorbid illnesses compete for patients’ time, attention, financial, and social resources. For example, patients with diabetes mellitus must check their blood sugar, adhere to a low carbohydrate diet, go to appointments for diabetes mellitus control, and (in some cases) take medications to control blood sugar. All of these activities may cause patients to place less absolute importance on HF and, therefore, detract from participation in an exercise training program.Depression is a key comorbid illness in HF. Depression is associated with reduced adherence to exercise training,12 although exercise is one of the few successful interventions among patients with depression and HF.2,13 In REHAB-HF, depression is particularly prominent in patients with HF with preserved ejection fraction and is clinically under-recognized (ie, depression was not mentioned in the patient’s chart, but the patient screened positive on the Geriatric Depression Scale, which was administered as part of the study). Depression may be clinically under-recognized in HF because it is difficult to treat. Antidepressants are often less effective for depression in HF patients, and cognitive behavioral therapy, one of the few efficacious interventions in this population,14 is not routinely available in most cardiology clinics. These challenges may lead to untreated depression reducing adherence in the REHAB-HF intervention arm.Cognitive impairment was present in a remarkable 78% of REHAB-HF participants. Cognitive impairment represents a challenge to HF self-care2; however, mild cognitive impairment (ie, objective memory loss but able to function in day-to-day life) in and of itself is not a barrier to exercise. Some data suggest that exercise improves cognitive performance.15 However, patients with cognitive impairment will require greater caregiver support for transportation and remembering to perform home exercises.HF-specific health status, as measured by the Kansas City Cardiomyopathy Questionnaire, is very poor among REHAB-HF participants. Poor Kansas City Cardiomyopathy Questionnaire scores reflect the highly symptomatic nature of these patients. Unfortunately, bothersome HF symptoms are associated with reduced adherence to exercise training.12 Therefore, ensuring excellent medical management of HF to minimize these symptoms may be important to exercise adherence.Physical frailty, as measured by the Fried criteria,16 was also highly prevalent among REHAB-HF participants (53%). Physical frailty is considered present if ≥3 Fried criteria are met: unintentional weight loss, exhaustion, slow gait speed, weak handgrip strength, or low physical activity.16 The effect of physical frailty on exercise adherence is not known in the HF population; however, the slow gait speed, weak handgrip strength, and low physical activity components of the Fried criteria would likely respond to exercise and to the REHAB-HF intervention in particular. The exhaustion and unintentional weight loss components of the Fried criteria may hinder exercise adherence. Final results of the REHAB-HF trial may shed more light on the interaction between physical frailty and adherence to exercise training.The REHAB-HF investigators are commended for designing an exercise intervention spanning the intersecting fields of geriatric cardiology, HF hospitalization, and exercise science. The high burden of comorbid illness and high prevalence of depression, cognitive impairment, debilitating HF symptoms, and physical frailty have wide-reaching implications, both for exercise therapy but also for geriatric HF care in general. Although we wait for the REHAB-HF trial to finish enrollment and follow-up, it seems prudent for clinicians caring for older adults with HF to promote physical activity and to consider strategies to overcome common noncardiovascular impediments in this vulnerable patient population.Whereas REHAB-HF is a clinical trial designed to specifically study the benefits of exercise training as a rigorous therapeutic intervention, multifaceted cardiac rehabilitation programs tailored to this population are still needed. Cardiac rehabilitation has complementary potential to emphasize critical aspects of adherence that are especially challenging amid geriatric impediments. A recent position paper defined 4 domains of geriatric HF care; physical function was only 1 of them.2 For patients to succeed in a rigorous exercise rehabilitation program like REHAB-HF, clinicians will need to address barriers in the other 3 domains (Medical, Mind and Emotion, and Social Environment). For example, careful, patient-centered deprescribing may decrease bothersome symptoms from polypharmacy that may deplete energy, blunt cognition, and exacerbate other impediments to daily activity. Alerting caregivers to a patient’s cognitive impairment, and thus need for greater supervision of day-to-day self-care activities, may help patients remain out of the hospital and provide them with the extra support needed to participate regularly in an exercise or rehabilitation program. Identification of financial or transportation problems may prompt clinicians to harness community resources to help patients and potentially suggest home- over site-based programs.The baseline characteristics of the first 202 REHAB-HF participants describe a vulnerable population with multiple comorbid illnesses and highly prevalent depression, cognitive impairment, bothersome HF symptoms, and physical frailty. These initial data not only describe the challenges faced by the REHAB-HF investigators in ensuring adherence to the REHAB-HF intervention, but they also represent a call to action for HF clinicians and investigators alike. Although we await the final trial results of REHAB-HF, we should focus on leveraging the detailed characterization of the REHAB-HF participants to improve the clinical care of, and development of novel interventions for, older adults hospitalized for HF.None.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Background:Obesity is highly prevalent among blacks and is associated with a greater risk of heart failure (HF). However, the contribution of regional adiposity depots such as visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue toward risk of HF in blacks is unknown.Methods and Results:We included 2602 participants (mean age: 59 years, 35% men) from the Jackson Heart Study without prevalent HF who underwent computed tomography quantification of VAT and subcutaneous adipose tissue during the second visit (2005–2009). The associations between different adiposity measures and HF were evaluated using adjusted Cox models. There were 122 incident HF events over a median follow-up of 7.1 years. Higher amounts of VAT were associated with greater risk of HF in age- and sex-adjusted analyses (hazard ratio [95% CI] per 1-SD higher VAT: 1.29 [1.09–1.52]). This association was attenuated and not significant after additional adjustment for traditional HF risk factors and body mass index. Overall obesity, represented by body mass index, was associated with higher risk of HF independent of risk factors and VAT (hazard ratio [95% CI] per 1-kg/m2 higher body mass index: 1.06 [1.02–1.11]). Subcutaneous adipose tissue was not associated with risk of HF in adjusted analyses.Conclusions:In a community-dwelling black population, higher amounts of overall and visceral adiposity are associated with higher risk of HF. The association between VAT and HF risk in blacks may reflect differences in traditional HF risk factor burden. Future studies are needed to confirm this observation and clarify the independent role of different measures of adiposity on HF outcomes.

Background:The STICH trial (Surgical Treatment for Ischemic Heart Failure) demonstrated a survival benefit of coronary artery bypass grafting in patients with ischemic cardiomyopathy and left ventricular dysfunction. The Surgical Thoracic Society (STS) risk score and the EuroSCORE-2 (ES2) are used for risk assessment in cardiac surgery, with little information available about their accuracy in patients with left ventricular dysfunction. We assessed the ability of the STS score and ES2 to evaluate 30-day postoperative mortality risk in STICH and a contemporary cohort (CC) of patients with a left ventricle ejection fraction ≤35% undergoing coronary artery bypass grafting outside of a trial setting.Methods and Results:The STS and ES2 scores were calculated for 814 STICH patients and 1246 consecutive patients in a CC. There were marked variations in 30-day postoperative mortality risk from 1 patient to another. The STS scores consistently calculated lower risk scores than ES2 (1.5 versus 2.9 for the CC and 0.9 versus 2.4 for the STICH cohort), and underestimated postoperative mortality risk. The STS and ES2 scores had moderately good C statistics: CC (0.727, 95% CI: 0.650–0.803 for STS, and 0.707, 95% CI: 0.620–0.795 for ES2); STICH (0.744, 95% CI: 0.677–0.812, for STS and 0.736, 95% CI: 0.665–0.808 for ES2). Despite the CC patients having higher STS and ES2 scores than STICH patients, mortality (3.5%) was lower than that of STICH (4.8%), suggesting a possible decrease in postoperative mortality over the past decade.Conclusions:The 30-day postoperative mortality risk of coronary artery bypass grafting in patients with left ventricular dysfunction varies markedly. Both the STS and ES2 score are effective in evaluating risk, although the STS score tend to underestimate risk.CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Background:Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important implications for candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients.Methods and Results:CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0–1 points) 4.8%, intermediate (2–4) 39.8%, and high risk (5–9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74).Conclusions:The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.

Background:Levels of cTn (cardiac troponin) are frequently elevated in patients with heart failure (HF) and reduced ejection fraction (EF) and correlate with the risk for mortality. However, factors associated with high cTn concentrations and the association with cardiovascular events in patients with HF and preserved EF are unclear.Methods and Results:Of 1767 subjects with symptomatic HF with preserved EF from the Americas part of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial), 236 underwent baseline measurements of high-sensitivity (hs) cTnI using the Abbott Architect STAT assay. Baseline factors correlated with hs-cTnI levels were assessed in stepwise linear regression models and the association between hs-cTnI and adjudicated study outcomes was examined in Cox models. The median hs-cTnI concentration at baseline was 6.3 ng/L (interquartile range, 3.4–12.9 ng/L) with levels detectable in 99.2% of patients. Higher hs-cTnI concentrations were associated with male sex, black race, lower estimated glomerular filtration rate and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. After multivariable adjustment, higher concentrations of hs-cTnI were associated with greater risk for the composite of cardiovascular death or HF hospitalization (69 events during mean follow-up 2.6±1.5 years): hazard ratio 1.42 (95% CI, 1.20–1.69), P<0.001 per doubling of hs-cTnI. Compared with those in the lowest quartile of hs-cTnI, patients in the highest quartile demonstrated a nearly 5-fold higher risk of cardiovascular death and HF hospitalization (hazard ratio 4.85 [1.99–11.83], P=0.001). There was no interaction between hs-cTnI and spironolactone treatment with regard to the primary composite end point (interaction P=0.94).Conclusions:In ambulatory patients with HF with preserved EF, levels of hs-cTnI are higher in male patients with black race, lower estimated glomerular filtration rate, and higher NT-proBNP. As in those with HF and reduced EF, higher hs-cTnI levels are independently associated with risk for cardiovascular death and HF hospitalization.CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.

In the article by Imamura et al, “Omega-3 Therapy Is Associated With Reduced Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device,” which appeared in the October 2018 issue of the journal (Circ Heart Fail.2018;11:e005082), a correction was needed.
In the Methods and Results section of the abstract, “4 mg/d of omega-3 therapy” should read “4 g/d of omega-3 therapy”.
The authors regret this error.
This correction has been made to the current version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.005082

See Article by Verdonschot et al
Establishing an accurate diagnosis, assessing prognosis, and managing treatment are fundamental to patient care. Clinical parameters, such as left ventricular (LV) ejection fraction and LV end-diastolic diameter, are critical to initially establish a diagnosis of dilated cardiomyopathy (DCM) and hypokinetic non-DCM. These clinical parameters are also used to monitor disease progression and treatment response. However, use of sequencing/genotyping technologies within the clinic is becoming more common in the era of personalized medicine. Efforts to sequence patients and classify the impact of mutations in cardiomyopathy-associated genes are helping to identify key diagnostic subgroups.
In this issue of Circulation: Heart Failure, Verdonschot et al1 studied the association between DCM and hypokinetic non-DCM patients’ genotype with improvement in reverse remodeling of the LV in response to medical therapy. The study defined reverse remodeling of the LV as an increase in LV ejection fraction and a decrease in LV end-diastolic diameter for ≈1 year of follow-up. Patients were genotyped using a custom panel of 47 genes associated with cardiomyopathy. Over 52% of the 346 patients studied had reverse remodeling of the LV after 12 months of treatment. Pathogenic gene mutations were found in 22% of patients (n=78). The most prevalent genes involved in these patients were titin (TTN, 9.5%) followed by lamin A/C (LMNA; 2.6%).
The findings of Verdonschot et al1 confirm and enhance the published literature,2–6 indicating that disease caused by mutations in LMNA are associated with a particularly severe form of DCM, with high arrhythmic burden, progression to end-stage heart failure, and here, lower likelihood of LV recovery. In contrast, disease caused by truncation mutations in titin (TTNtv) is associated with more mild disease that seems more responsive to unloading therapy,7–9 and thus more likely to favorably remodel and recover with standard medical therapy for heart failure. Furthermore, because of the large size of titin and the presence of multiple isoforms, the location of variants within the gene also plays a role in determining DCM disease burden. TTNtv localized towards the N terminus, affecting certain TTN isoforms (N2B and N2BA), and within exons commonly removed during splicing have been associated with a more mild or no pathology,10 whereas variants located in commonly expressed exons (and thus, translated into the final protein product) are predicted to be pathogenic.9 These findings underscore that genotype can influence the clinical decision-making process and that differentiating clinically relevant subgroups of DCM, guided by genetic cause, may play an important role in diagnosis, prognosis, and management. From an academic perspective, gaining greater understanding in gene- and variant-specific mechanisms will undoubtedly lead to advances in our understanding of how protein-protein domain perturbations,11 changes in mRNA splicing,12 and protein functional changes13 contribute to in disease pathogenesis. This information will be critical to identify molecular mechanisms leading to DCM and to design targeted drug therapies to treat distinct genetic subclasses of DCM pathology.
The genetic basis of DCM/hypokinetic non-DCM also has important clinical implications. Receipt of genetic results is a reminder to think about the patient’s family in addition to the individual presenting for care in clinic.14 If there is no clear explanation for why cardiomyopathy developed, a detailed family history should be obtained, and first-degree relatives should be screened to evaluate for familial disease.15 Although the genetic cause of DCM is diverse and incompletely resolved and the yield of clinical genetic testing is currently relatively modest (a genetic cause can be detected ≈20% of the time),15,16 identifying a pathogenic mutation in a patient provides unique and valuable information to guide management of the patient and their family. At-risk relatives can be definitively identified and followed appropriately. Relatives not at risk can be reassured. Affected individuals can be given more precise prognostic forecasts, and more aggressive therapy can be steered towards those predicted to have more aggressive disease, based on genetic substrate. The work of Verdonschot et al1 highlight that adding genetic information, in addition to clinical parameters, may better predict reverse remodeling of the LV than clinical parameters alone. Linking the degree of disease burden to variants (and properly defining variants of unknown significance) is still necessary. Efforts in linking disease burden to variants will ultimately lead to improvements in patient care and in our understanding of cardiomyopathies.
None.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Background:Stroke prophylaxis in patients with atrial fibrillation (AF) and heart failure (HF) in the era of direct oral anticoagulants is not well characterized. Using data from American Heart Association Get With The Guidelines–AFIB, we sought to evaluate oral anticoagulation (OAC) use at discharge among AF patients with concomitant HF.Methods and Results:AF patients with a diagnosis of HF hospitalized from January 2013 to March 2017 were included. We compared patient characteristics and use of OAC at discharge among patients with reduced (redundant ejection fraction [EF], EF≤40%), borderline (40%

The American Heart Association convened a meeting to summarize the changing landscape of heart failure (HF), anticipate upcoming challenges and opportunities to achieve coordinated identification and treatment, and to recommend areas in need of focused efforts. The conference involved representatives from clinical care organizations, governmental agencies, researchers, patient advocacy groups, and public and private healthcare partners, demonstrating the breadth of stakeholders interested in improving care and outcomes for patients with HF. The main purposes of this meeting were to foster dialog and brainstorm actions to close gaps in identifying people with or at risk for HF and reduce HF-related morbidity, mortality, and hospitalizations. This report highlights the key topics covered during the meeting, including (1) identification of patients with or at risk for HF, (2) tracking patients once diagnosed, (3) application of population health approaches to HF, (4) improved strategies for reducing HF hospitalization (not just rehospitalization), and (5) promoting HF self-management.

Background:Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)—a novel ubiquitin-like protein—has not been explored in either the normal or stressed heart.Methods and Results:Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)—an enzyme essential for Ufm1 modification—was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction.Conclusions:Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.

See Article by J. Li et al
Defects in protein homeostasis (also known as proteostasis) are intrinsically linked to age-related decline of cardiac function and likely contribute to cardiomyopathies. Protein-folding chaperones and protein quality control systems work overtime in the high stress cardiac environment, responding to wear and tear. Tight regulation of the pathway components is often controlled by posttranslational modifications. In addition to compact posttranslational modifications such as phosphorylation, bulkier posttranslational modifications involve Ub (ubiquitin) and other small UbL (Ub-like) proteins, which are covalently conjugated to target proteins. These modifications can affect stability, localization, and function of the target protein. Ufm1 (ubiquitin-fold modifier 1) is a less-studied UbL, but modification by Ufm1 (ufmylation1) is emerging as an important mediator of the endoplasmic reticulum (ER) stress response, which is activated in cardiomyocytes during heart failure. Focusing on Ufl1 (Ufm1-ligase 1), one of the enzymes that mediate ufmylation, the report from Li et al2 provide strong evidence that Ufl1 has a cardioprotective role and points to the ufmylation pathway as a potential target for pharmacological intervention for some cardiomyopathies.
Ub and UbLs share a common biology in the way they are added to targets and recycled in the cell, but each class tends to have specialized roles.3 They are varied in their individual protein sequences, with Ub/UbLs sharing a common structural fold as revealed by crystallographic as revealed by protein crystallographic studies. After synthesis as a pro-protein, Ub/UbLs are cleaved at the C terminus by a protease, a prerequisite for entering the conjugation cycle. The cleaved Ub/UbL is engaged by an activation enzyme (generically termed E1 or enzyme 1). Via this Ub-E1 intermediate, the Ub/UbL is then passed to a conjugating enzyme (E2 or enzyme 2). In some cases, the E2 can engage directly with target proteins, and the Ub/UbL is conjugated by its C terminus to the targets, usually to a lysine. In most cases, however, the Ub-E2 intermediate engages with a ligating enzyme (or E3 ligase; enzyme 3). The structure of the E3 may vary greatly, from being a single protein to a multiprotein complex, but in general, the E3 serves to enhance delivery of the mature Ub/UbL to a lysine on specific target proteins. Certain conserved protein domains are characteristic of E3 ligases (eg, RING [really interesting new gene] or HECT [homologous to the E6-AP carboxyl terminus] domains), and by this measure, it is estimated that >600 E3 Ub/UbL ligases are encoded by the human genome. Other E3 ligases have been described that lack these domains but may function as scaffolding adaptors to bridge the E2-Ub/UbL and targets (Ufl1, featured in Li et al,2 is one example). Ub/UbL posttranslational modifications vastly increase the complexity of the human proteome and require exquisite regulation to allow cells to cycle, survive, and respond to signals and stress.
Correct regulation of proteostasis underlies both healthy and diseased/damaged heart function. This complex task balances protein synthesis, folding, and degradation, with the latter relying on multiple systems (autophagy, calpains, proteasomes4,5). Specifically, contributions to cardiac proteostasis by the Ub-proteasome system have been extensively reviewed.6,7 Cardiac roles for modifications by other UbLs (NEDD8 [neural precursor cell expressed, developmentally down-regulated 8], SUMO [small ubiquitin modifier]) have also been described.8,9 Many of the studies defining cardiac roles for Ub/UbL modifications rely on either classical or conditional knockout mice, with the latter allowing heart-specific deletion of the genes encoding the UbL or its associated pathway enzymes. These precise genetic studies allow molecular, histological, and physiological analysis of the heart in experimental animals. When coupled with surgical methods to induce heart stress or with drug administration or both, such studies can reveal promising targets and therapies for future clinical trials.
Ufmylation was discovered by chance in a search for proteins implicated in autophagy,10 and like ubiquitylation, it occurs through a multienzyme cascade (Figure). The E1-activating enzyme Uba5 (ubiquitin like modifier activating enzyme 5) was identified first, and further biochemical and proteomic analysis revealed Ufm1 as the novel UbL that is activated by Uba5. The same study also discovered the dedicated E2 enzyme, Ufc1 (UFM1 conjugating enzyme 1), responsible for conjugation of Ufm1 to target proteins. Later studies uncovered Ufl1, a Ufm1 E3 ligase, as an interactor of both Ufm1 and the E2 Ufc1.11 The search for proteases that were capable of processing pro-Ufm1 and that could remove and recycle Ufm1 from target proteins yielded 2 related proteins, Ufsp1 and Ufsp2 (UFM1 specific peptidase 1 and 2).12 All of these proteins show close association to the ER, and functional studies (including the present report) point to specialized roles for ufmylation in regulating ER-related stress. The ER is a major site of protein quality control, housing the synthesis machinery for proteins destined to be secreted or membrane-trafficked within the cell, as well as chaperones to assist protein folding and 3 separate systems (PERK [protein kinase R-like ER kinase], ATF6 [activating transcription factor 6], IRE1 [inositol-requiring enzyme 1]) that mediate the unfolded protein response. Several ufmylated target proteins have been identified, although these are few in number compared with those modified by Ub or SUMO. One ufmylated target, Ufbp1 (also known as Ddrgk1 [DDRGK domain containing 1]), warrants particular mention since it is required for efficient ufmylation of other targets and may act as a cofactor for the Ufl1 E3 ligase. Loss-of-function classical knockouts in mice (Uba5, Ufl1, or Ufbp1) have revealed an essential role for ufmylation in erythroid development and lead to embryonic lethality.1 Tissue-specific knockouts can be used to reveal roles later in development, exemplified by Li et al.2 This approach has uncovered a novel role for Ufl1 in mouse cardiac health.
Figure. Features of the ufmylation cycle, a key pathway for endoplasmic reticulum (ER)-based stress response in cardiac development and disease. UFM1 (ubiquitin-fold modifier 1) is conjugated to substrates through a multienzyme cascade. After proteolytic maturation, UFM1 is passed via 3 enzymes (activating E1, conjugating E2, and ligating E3) as it attaches to substrates. Specific proteases remove and recycle Ufm1. Li et al2 demonstrate that Ufl1 (Ufm1-ligase 1), a Ufm1 E3 ligase, is cardioprotective in both physiological and pathological conditions. How ufmylation influences substrates, whether E3 ligases are obligatory, whether additional E3 ligases exist, and how the Ufbp2 cofactor affects E3 activity are still open questions for future investigation. Even so, the ufmylation pathway may offer unique drug targets for cardiac and other diseases that feature ER stress response as cause or consequence of the pathology. ATP indicates adenosine tri-phosphate; Ufbp1, UFM1-specific binding protein 1; and Ufc1, UFM1 conjugating enzyme 1.
Their study begins with the observation that, although ufmylation of major target proteins in the heart seems to increase over time (from 1-day to 1-year old), levels of Ufl1 E3 ligase seem to decrease. This may seem counterintuitive, but possible explanations may lie in altered levels or activities of other ufmylation mediators (Uba5, Ufc1, Ufbp1, Ufsp1/2). Upon surgically induced cardiac hypertrophy in mice, levels of both ufmylation and Ufl1 increased. Levels of Ufl1 decreased during induced ischemia/reperfusion, likely because of cardiomyocyte death. Samples from patients with dilated cardiomyopathy also showed reduced Ufl1 levels, all leading to the hypothesis that ufmylation might be a key player in cardiac stress response. To address this, the authors used a conditional mouse mutant to remove Ufl1 from the cardiomyocyte population, to see how this affected both normal heart development, as well as response to heart stress and injury.
While Ufl1 levels were significantly reduced in whole heart extracts from knockouts, detectable Ufl1 and ufmylation still remained, suggesting that genetic removal was not complete, or that noncardiomyocyte cells contribute to residual activity. Alternatively, as seen with SUMOylation, perhaps ufmylation of some targets does not require an E3 ligase, or perhaps another uncharacterized Ufm1 E3 ligase acts redundantly to Ufl1 (Figure). Still, reduction of Ufl1 was sufficient to induce cardiac remodeling and progressive functional deterioration as measured by echography, histology, and changes in gene expression. Using induced cardiac hypertrophy, Ufl1CKO mice were unable to make compensatory changes and developed heart failure, with increased fibrosis and decreased contractility, suggesting that Ufl1 has a cardioprotective role.
Turning to molecular mechanisms, comparative analysis of transcriptomes from control and Ufl1CKO mice pointed to ER dysfunction when Ufl1 was reduced. Indeed, as reported previously for cells and other organ systems, loss of Ufl1 and ufmylation in the heart leads to increased ER stress, evident as an increase in stress response chaperones and changes in ER ultrastructure. Induced cardiac hypertrophy also induced stress chaperones, but the same treatment in Ufl1CKO mice led to even higher levels. Using primary cardiomyocytes from rat and drugs to induce ER stress, the authors show that at least 1 of 3 unfolded protein response pathways (PERK) was affected by Ufl1 reduction. Using a previously reported strategy,13 administration of tauroursodeoxycholic acid, a chemical chaperone known to alleviate ER stress, was able to reduce the cardiac enlargement and ER stress-induced cell death seen in Ufl1CKO mice with surgically induced cardiac hypertrophy. Overall, the results convincingly show that Ufl1 and ER stress regulation are tightly connected and that ufmylation may be a druggable cardioprotective pathway.
Although tauroursodeoxycholic acid is being testing in clinical trials, including some focused on cardiac issues (eg, https://www.clinicaltrials.gov. Unique identifier: NCT01855360), a treatment more focused on Ufl1 and the ufmylation pathway may yield less secondary effects. Given the current push to exploit E3 ligases and deubiquitinases as druggable targets,14,15 the ufmylation pathway will certainly be explored and new drug candidates will likely emerge in the upcoming years. Li et al2 suggests that activation of ufmylation would be beneficial in the case of some cardiomyopathies and perhaps age-related decline of cardiac health. A better understanding of how Ufl1 interacts with targets for ufmylation and how Ufsp1 (the potential Ufl1 cofactor; Figure) contributes to the E3 activity of Ufl1 may lead to new ideas on how to find or design activating compounds. Activators of Uba5 and Ufc1 could also lead to overall increases of ufmylation. Conversely, a search for inhibitors of Ufm1 proteases may identify a compound capable of enriching for ufmylated proteins. A recent report shows that the loss of Ufsp2 in cells leads to a dramatic increase in ufmylated targets,16 suggesting that inhibitors may yield the desired effect. Since heart failure is a leading cause of morbidity and mortality, especially among middle-aged and older adults, this important study reveals ufmylation as a promising pathway to explore for therapeutic benefits in cardiomyopathies and likely other ER stress-based illnesses.
Drs Sutherland and Barrio are funded by BFU2017-84653-P (MINECO/FEDER, EU), the Severo Ochoa Excellence Program (SEV-2016- 0644), the UbiCODE program (765445, EU) and PROTEOSTASIS (COST BM1307, EU). Additional support was provided by the Department of Industry, Tourism, and Trade of the Government of the Autonomous Community of the Basque Country (Elkartek Research Programs) and by the Innovation Technology Department of the Bizkaia County.
None.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
https://www.ahajournals.org/journal/circheartfailure

Primary angiosarcoma of the pericardium is exceptionally rare, and diagnosis remains challenging because of the variability of its clinical presentation. Here, we report a case of a 26-year-old woman with pericardial angiosarcoma who presented with recurrent hemorrhagic pericardial effusion diagnosed at histopathologic examination.
A 26-year-old female patient had a 4-month history of dyspnea, chest pain, cough, palpitation, and fatigue. Echocardiography revealed pericardial effusion. However, no obvious mass was identified either in the pericardium or in the heart. Pericardiocentesis and drainage were performed 3×, draining 700 mL of hemorrhagic pericardial effusion. The patient’s symptoms improved after percutaneous drainage of bloody pericardial fluid. The effusion cultures for bacteria, acid-fast bacilli, and viruses were always negative. Repeated cytological examination of the pericardial effusion did not show malignant cells. Her dyspnea and cough recurred after 2 months. Echocardiography showed thickened pericardium and mild pericardial effusion. The patient was empirically treated for tuberculous pericarditis, considering the unexplained hemorrhagic pericardial effusion and the high incidence of tuberculous pericarditis in China. After 1 month, she did not respond to antituberculous therapy, and her clinical condition rapidly deteriorated. Therefore, she was referred to our institution for further examination.
On physical examination, her pulse rate, respiration rate, and blood pressure were 127 beats per minute, 22 per minute, and 117/65 mm Hg, respectively. Kussmaul sign and paradoxical pulse were present. No cardiac murmur or pericardial rub was detected.
Chest radiograph showed marked cardiomegaly (Figure [A]). Transthoracic echocardiography revealed a huge mass in the pericardium surrounding and compressing the ventricles, atria, ascending aorta, and pulmonary trunk (Figure [B] and [C]; Movies I through III in the Data Supplement). Her echocardiography demonstrated septal bounce and dilation and diminished collapse of the inferior vena cava. Color Doppler flow imaging showed mild tricuspid regurgitation (Figure [D]; Movie IV in the Data Supplement). Pulsed-wave Doppler echocardiography demonstrated that peak mitral E inflow decreased (>25%) after inspiration (Figure [E]). High enhancement of contrast agent in the pericardial mass was noted after contrast echocardiography (Figure [F]; Movie V in the Data Supplement). Chest computed tomography showed that the entire heart was encased by the pericardial mass. Cardiac magnetic resonance imaging revealed that the large mass within the pericardium surrounded and severely compressed the entire heart and great vessels. On T1- and T2-weighted cardiac magnetic resonance images, the pericardial mass appeared heterogeneous and hyperintense relative to the myocardium (Figure [G], [H], and [I]). After intravenous contrast with gadopentetate dimeglumine, enhancement was observed as multiple lines in the tumor radiating from the epicardium to pericardium (a sunray appearance; Figure [J]). Positron emission tomography revealed a neoplastic mass in the pericardium (Figure [K]). Distant metastases were found only in the lymph node of the right cardiophrenic angle and the left musculus obliquus externus abdominis (Figure [L]).
Figure. Multimodal imaging and pathological findings.A, Chest radiograph showing marked cardiomegaly. B and C, Transthoracic echocardiography showing a large pericardial mass surrounding and compressing ventricles and atria. D, Color Doppler flow imaging indicates mild tricuspid regurgitation. E, Pulsed-wave Doppler echocardiography demonstrates that peak mitral E inflow decreased (>25%) after inspiration. F, Contrast echocardiography showing high enhancement of contrast agent in the pericardial mass. G, The pericardial mass appears heterogeneous and hyperintense relative to the myocardium on T1-weighted cardiac magnetic resonance (CMR) images. H and I, The pericardial mass is heterogeneous and hyperintense on T2-weighted CMR images. J, Enhanced CMR imaging reveals multiple lines in pericardial tumor, radiating from the epicardium to pericardium (sunray appearance). K and L, Positron emission tomography reveals a neoplastic mass in the pericardium and distant metastases. Ao indicates aorta; Ee, E velocity during expiration; Ei, E velocity during inspiration; LA, left atrium; LV, left ventricle; M, mass; RA, right atrium; and RV, right ventricle.
Open biopsy was performed for a definitive diagnosis. Histopathologic examination showed a malignant tumor. Immunohistochemical staining indicated that these cells were positive for CD (cluster of differentiation) 31, CD34, ETS-related gene, and Ki67. Hence, the overall findings were consistent with pericardial angiosarcoma. The patient refused chemotherapy and radiotherapy, considering the distant metastases of pericardial angiosarcoma and poor prognosis, and she died after 2 months.
Primary cardiac tumors are rare entities (0.0017%–0.003% of routine autopsy studies, 25% malignant).1 Cardiac angiosarcomas, although rare, are the most common primary malignant cardiac tumors (31% of all malignancies).2 They tend to be found in patients aged 20 to 50 years and are more common in men.3 Most cases are more often found in the right atrium, making pericardial angiosarcoma extremely rare. Pericardial angiosarcomas respond poorly to chemotherapy. Prognosis is poor, with mean survival time of 6 to 11 months.4
Making an accurate diagnosis remains challenging because its clinical presentation is variable, and available noninvasive imaging modalities lack specificity. Echocardiography, although frequently performed, plays a limited role in the evaluation of primary pericardial angiosarcoma. Echocardiography frequently demonstrates pericardial effusion but may not show a mass because it depends on good acoustic window. Pericardiocentesis commonly yields hemorrhagic fluid that does not contain malignant cells, as seen in our case. Computed tomography demonstrates the location, size and extent of the tumor, and its invasion of vital structures. Cardiac magnetic resonance imaging is a more powerful tool for characterizing the lesion. Cardiac magnetic resonance imaging may also demonstrate constrictive physiology with diffuse thickening of the pericardium. Positron emission tomography may be a useful tool because it may demonstrate distant or locoregional metastatic disease. Detecting this malignant tumor in the early stage may be challenging, despite the application of various advanced imaging modalities.
We describe a case of a patient with pericardial angiosarcoma who presented with recurrent hemorrhagic pericardial effusion that rapidly progressed in a short period. Our case indicates that unexplained hemorrhagic pericardial effusion should prompt the clinician to seek for a malignant etiology, even when malignant cells are not found on fluid cytology.
This work was supported by the National Natural Science Foundation of China (No. 81401432 and 81727805).
None.
https://www.ahajournals.org/journal/circheartfailure
The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.118.005342.

BackgroundGastrointestinal bleeding (GIB) is a common complication seen in patients supported with left ventricular assist devices (LVADs) and is related to increased inflammation and angiogenesis. Omega-3 is an unsaturated fatty acid that possesses anti-inflammatory and antiangiogenic properties. This study aims to assess the prophylactic efficacy of treatment with omega-3 on the incidence of GIB in LVAD patients.Methods and ResultsAmong consecutive 166 LVAD patients enrolled in this analysis, 30 patients (49 years old and 26 male) received 4 mg/d of omega-3 therapy for 310±87 days and 136 patients in the control group (58 years old and 98 male) were observed for 302±102 days. One-year GIB-free rate was significantly higher in the omega-3 group as compared with the control group (97% versus 73%; P=0.02). Omega-3 therapy was associated with the occurrence of GIB in both the univariate (hazard ratio, 0.12; 95% CI, 0.02–0.91; P=0.040) and multivariate Cox proportional hazard ratio analyses (hazard ratio, 0.13; 95% CI, 0.02–0.98; P=0.047). The frequency of GIB was significantly lower in the omega-3 group (0.08±0.42 versus 0.37±0.93 events/y; P=0.01), accompanied by significantly lower blood product transfusion and shorter days in the hospital. The frequency of GIB remained lower among the omega-3 group after matching for patient background characteristics (96% versus 73%, P=0.028).ConclusionsLVAD patients treated with omega-3 had a significant increase in freedom from GIB. A randomized controlled study is warranted to evaluate the use of omega-3 in LVAD patients.

The United Network for Organ Sharing will implement changes to the adult heart allocation system this fall. Adults supported by Venoarterial extracorporeal membrane oxygenation (VA ECMO) will be eligible for the highest status listing during the first 7 days, and for status 2, from the seventh through 14th day of support, renewable thereafter.1 The new policy strives to reduce wait-list mortality by prioritizing heart allocation to the most critically ill. Many have raised concerns about the status of ECMO in the new allocation scheme with regards to its impact on organ allocation. But there is an elephant in the room. Is VA ECMO ready for prime time as the standard of care for managing profound cardiogenic shock in the United States?
Since the first ECMO intervention in 1972, the extracorporeal life support family of therapies has evolved. In 1989, therapeutic advances in extracorporeal life support contributed to the formation of a scientific platform, the Extracorporeal Life Support Organization. In the year 2017, 379 centers provided ECMO therapy worldwide, a number that has steadily increased from 83 in 1990.2 The ECMO financial market is anticipated to reach USD 305.3 million by 2021 from USD 247.2 million in 2016.3
However, despite the advances, ECMO therapy faces several challenges. The management of patients on ECMO remains complex and resource intense. As a result, the use of ECMO remains restricted to specialized centers with center-specific utilization protocols. Ironically, to date, there is not a single blood pump with Food and Drug Administration approval for providing >6 hours of circulatory support, in a VA ECMO configuration, for patients with cardiogenic shock from left ventricular or combined right and left ventricular failure.
The paradigm shift in heart allocation policy should serve as a call to action to transform advances in extracorporeal life support therapy to standards of care for managing profound cardiogenic shock and refractory cardiac arrest. To accomplish this, a multifaceted approach is suggested as follows: (1) at the healthcare delivery level, a system based approach should integrate ECMO into existing networks of ST-segment–elevation myocardial infarction care. Hub and spoke models for advanced heart failure care must be clearly delineated such that community cardiology centers establish efficient channels of communication and transfer mechanisms to advanced heart failure centers for patients on or in need for ECMO support. (2) At the scientific level, working knowledge of extracorporeal life support therapies should be integrated into resident and fellow training curricula across multiple specialties. Key scientific societies need to collaboratively update recommendations for VA ECMO therapy and monitor utilization via a single registry. The American Heart Association needs to work toward taking the Mission: Lifeline to the next level by incorporating ECMO assisted cardiopulmonary resuscitation for refractory cardiac arrest. (3) At the regulatory level, the Food and Drug Administration needs to ensure that the process of applying for ECMO product labeling is conducive to inviting competition from the industry to help curtail cost and deal with future supply shortages. (4) At the industry level, manufacturers need to gear up for innovations to make ECMO safer for longer-term support, resource efficient, portable, and cost effective.
I think the status of ECMO in the new United Network for Organ Sharing scheme is well intended. Given the severity of illness of patients requiring ECMO support, its impact on heart allocation may be less than generally perceived. More importantly, we need to get our act together to make VA ECMO an accessible standard of care across the United States. In my opinion, the implications of the latter will be far greater.
None.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
https://www.ahajournals.org/journal/circheartfailure

Background:Heart failure (HF) is often associated with iron deficiency (ID). Skeletal muscle abnormalities are common in HF, but the potential role of ID in this phenomenon is unclear. In addition to hemopoiesis, iron is essential for muscle bioenergetics. We examined whether energetic abnormalities in skeletal muscle in HF are affected by ID and if they are responsive to intravenous iron.Methods and Results:Forty-four chronic HF subjects and 25 similar healthy volunteers underwent 31P magnetic resonance spectroscopy of calf muscle at rest and during exercise (plantar flexions). Results were compared between HF subjects with or without ID. In 13 ID-HF subjects, examinations were repeated 1 month after intravenous ferric carboxymaltose administration (1000 mg). As compared with controls, HF subjects displayed lower resting high-energy phosphate content, lower exercise pH, and slower postexercise PCr recovery. Compared with non-ID HF, ID-HF subjects had lower muscle strength, larger PCr depletion, and more profound intracellular acidosis with exercise, consistent with an earlier metabolic shift to anaerobic glycolysis. The exercise-induced PCr drop strongly correlated with pH change in HF group (r=−0.71, P<0.001) but not in controls (r=0.13, P=0.61, interaction: P<0.0001). Short-term iron administration corrected the iron deficit but had no effect on muscle bioenergetics assessed 1 month later.Conclusions:HF patients display skeletal muscle myopathy that is more severe in those with iron deficiency. The presence of ID is associated with greater acidosis with exercise, which may explain early muscle fatigue. Further study is warranted to identify the strategy to restore iron content in skeletal muscle.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO)—also referred to as extracorporeal life support—is a form of temporary mechanical circulatory support and simultaneous extracorporeal gas exchange. The initiation of VA-ECMO has emerged as a salvage intervention in patients with cardiogenic shock, even cardiac arrest refractory to standard therapies. Analogous to veno-venous ECMO for acute respiratory failure, VA-ECMO provides circulatory support and allows time for other treatments to promote recovery or may be a bridge to a more durable mechanical solution in the setting of acute or acute on chronic cardiopulmonary failure. In this review, we provide a brief overview of VA-ECMO, the attendant physiological considerations of peripheral VA-ECMO, and its complications, namely that of left ventricular distention, bleeding, heightened systemic inflammatory response syndrome, thrombosis and thromboembolism, and extremity ischemia or necrosis.

BackgroundCurrent guidelines recommend sacubitril/valsartan for patients with heart failure with reduced ejection fraction, but the rate of adoption in the United States has been slow.Methods and ResultsUsing data from CHAMP-HF (Change the Management of Patients With Heart Failure), we described current sacubitril/valsartan use and identified patient, provider, and practice characteristics associated with its use. We considered patients to be on sacubitril/valsartan if they were prescribed it before enrollment or initiated on it at the baseline visit. We excluded patients with a contraindication to sacubitril/valsartan and practices with <10 patients enrolled. Of 4216 patients from 121 sites, 616 (15%) were prescribed sacubitril/valsartan, 2506 (59%) an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), and 1094 (26%) neither. Patients prescribed sacubitril/valsartan were younger (63 years versus 66 years ACE inhibitor/ARB versus 69 years neither, P<0.001), less likely to have chronic kidney disease (15% versus 17% ACE inhibitor/ARB versus 30% neither, P<0.001), more likely to have cardiac resynchronization therapy (12% versus 7% ACE inhibitor/ARB versus 7% neither, P<0.001), and had lower ejection fraction (27% versus 30% ACE inhibitor/ARB versus 30% neither, P<0.001). Larger practices, based on number of cardiologists and advanced practice providers, were associated with the highest sacubitril/valsartan use. After multivariable adjustment, the number of advanced practice providers was associated with sacubitril/valsartan use (adjusted odds ratio,1.08; 95% CI, 1.03–1.14).ConclusionsDespite current guideline recommendations, adoption of sacubitril/valsartan remains low. Provider and practice characteristics associated with sacubitril/valsartan use were related to general practice size and were not associated with practice characteristics specific for heart failure. Further research is needed to identify strategies for effective quality improvement interventions in chronic heart failure with reduced ejection fraction.

See Article by Bartoli et al
This is your last chance. After this, there is no turning back. You take the blue pill—the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill—you stay in Wonderland and I show you how deep the rabbit-hole goes.
—Morpheus in The Matrix1
The advent of continuous flow left ventricular assist devices (CF LVADs) for end-stage heart failure has led to marked improvements in survival, device miniaturization and durability, yet serious adverse hematologic events limit this therapy. Although changes in CF LVAD design have led to a reduction in device thrombosis, gastrointestinal bleeding (GIB) remains a major source of morbidity occurring in ≈30% of patients.2,3
The exact pathophysiology of GIB during CF LVAD remains unclear, but it has become apparent that 2 major factors contribute toward excessive bleeding: (1) a hematologic disturbance, specifically an acquired von Willebrand factor (VWF) syndrome (avWs) and (2) angiodysplasia formation in the gastrointestinal tract. VWF is a glycoprotein synthesized in endothelial cells (ECs) and megakaryocytes that undergoes post-translational modification to form ultralarge or high-molecular-weight multimers (HMWMs).4 These HMWMs are stored in the Weibel Palade bodies of ECs and platelets and released in response to hemorrhage. On release, HMWMs serve as bridges crosslinking exposed collagen and platelets to form a platelet plug at the site of injury within a blood vessel.4 HMWMs are cleaved by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) into smaller multimers at its A2 domain. Although VWF multimers of all sizes contribute to coagulation, the larger the multimer, the greater the hemostatic potential. Increased shear stress, as produced by CF LVADs, elongates the multimers and causes changes in the conformation of the A2 domain making it more susceptible to cleavage by ADAMTS13.5 Thus, shear forces generated during passage of blood elements through a CF LVAD accelerate degradation of HMWMs via increased proteolysis and to create avWs.
Although various subtypes of von Willebrand disease were known to be associated with angiodysplasia, novel in vitro studies by Starke et al6 further demonstrated VWF as a negative regulator of angiogenesis. In their investigation, inhibition of VWF expression in human umbilical vein ECs by siRNA led to an increase in VEGF (vascular endothelial growth factor)-dependent cell proliferation, migration, and tubule formation.6 It was suggested that VWF inhibits angiogenesis through the following 2 spatially separate mechanisms: (1) extracellular binding of VWF to integrin αvβ3 reduced VEGF-2–dependent proliferation of ECs and (2) defective Weibel Palade body formation from loss of VWF led to ineffective intracellular storage and unregulated release of Ang-2 (angiopoietin-2), thereby creating angiodysplasia.6,7
Further investigation into dysregulated angiogenesis has shed some light toward a possible pathogenesis of angiodysplasia during CF LVAD support. Tabit et al reported higher levels of thrombin induced Ang-2 in patients with a CF LVAD. Moreover, antibody blockade of Ang-2 resulted in a reduction of tubule formation by human umbilical vein ECs after exposure to serum from CF LVAD patients.8 Additionally, retrospective studies have associated angiotensin-converting enzyme inhibitors/angiotensin receptor blockers9 and digoxin10—medications that can reduce Ang-2 levels—with reduced angiodysplasia-related GIB during CF LVAD support.
In this issue of Circulation: Heart Failure, Bartoli et al11 further relate avWs to clinical bleeding and propose a potentially unifying mechanism that associates VWF multimer loss and fragment formation to the development of angiodysplasia during CF LVAD support. The authors confirm previous findings12 and show a reduction in HMWMs with an increase in low-molecular-weight multimers, irrespective of clinical bleeding events. More interestingly, they note greater levels of VWF 450-kDA fragments in 7 (20%) patients who experienced an angiodysplasia-related GIB in comparison with nonbleeders (P=0.02).11 To further investigate the relation between VWF multimers and angiodysplasia, they assess tubule length and migration of human umbilical vein ECs plated on matrigels with (1) exposure of fragment-rich whole blood from CF LVAD patients and (2) addition of 450-kDA VWF fragments isolated from a shear stress mock loop. In both experiments, there is reduction in tubule length and migration as compared with pre-CF LVAD controls. Overall, the authors conclude that CF LVAD-related shear stress creates VWF fragments, which in turn are associated with angiodysplasia and ultimately lead to the clinical manifestation of mucosal bleeding.
The investigators are to be commended for exploring a multifaceted and prevalent device-related adverse event in a prospective method on both clinical and mechanistic levels. An enigmatic clinical inquiry into device-related GIB has been why bleeding does not occur in all patients exposed to a CF LVAD since all patients develop avWs. In this study, Bartoli et al offer some granularity by proposing for the first time specific phenotypes of CF LVAD-related avWs, defined by a ratio of VWF multimers to fragments. With precise phenotypic identification, there could be potential for identifying at-risk individuals and developing targeted therapy, which would be a major step toward addressing the current Achilles heel of CF LVADs; yet, caution must be exercised, and findings must be framed within the scope of the present methodology aimed only at associating VWF profile with angiodysplasia.
Although it is interesting that patients with elevated VWF fragments shortly after LVAD implantation were noted to develop angiodysplasia-related bleeding, and in an in vitro experiment, isolated VWF fragments reduced tubule formation, the authors rightly mention that such results may not implicate in vivo causality. In the ex vivo experiment, with exposure of fragment-rich whole blood from CF LVAD patients to human umbilical vein ECs, there is reduced tubule formation, but it is uncertain whether there are other antiangiogenic mediators that may impede normal microvessel development. More pressing is the uncertainty in reconciling the matrix, that is, the role of decreased in vitro tubule formation related to VWF fragments and increased tubule formation with loss of VWF/elevated Ang-2, as shown in previous studies,6,8 toward angiodysplasia formation. In other words, whether VWF fragment associated reduction in tubule formation and migration is indeed equivalent to in vivo CF LVAD-related angiodysplasia bleeding remains to be further established.
As with any intriguing findings, there tend to be more questions than answers. A few queries at the forefront are as follows: (1) Why do only a subset of CF LVAD patients form VWF fragments? (2) How do VWF fragments prevent normal microvessel formation? (3) What is the role of pulsatility in determining the VWF profile, as recent animal model studies suggest preservation of HMWMs under pulsatile conditions?13 (4) Is there device-specific VWF fragment formation? and (5) How can this VWF fragment-related hypothesis be integrated with the recent observation that small bowel mucosal angiodysplasia may precede CF LVAD implantation?14 Moreover, if VWF profile is related to GIB, since differing VWF breakdown patterns are reported among various CF LVADs,15 there should be differences in the prevalence of GIB between such devices; but this was not reported in the 2-year outcomes of the MOMENTUM trial (The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3).2 Though likely not the sole culprit toward angiodysplasia-related GIB, perhaps knowledge of VWF fragment formation may eventually inform therapeutic use of downstream antiangiogenic mediators and tailored anticoagulation therapies to modify disease burden. Bartoli et al11 have made another important contribution to exploration of the von Willebrand matrix, but the mechanistic underpinnings of GIB in CF LVAD are yet to be fully elucidated. For now, we shall take the red pill with a few video capsules and remain in wonderland.
Dr Jorde is a nonpaid consultant to Abbott. The other authors report no conflicts.
https://www.ahajournals.org/journal/circheartfailure
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

BackgroundAlthough atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) patients, the relationship between genetic variation and AF has been poorly defined. Characterizing genetic subtypes of HCM and their associations with AF may help to improve personalized medical care. We aimed to investigate the link between sarcomeric gene variation and incident AF in HCM patients.Methods and ResultsPatients from the multinational Sarcomeric Human Cardiomyopathy Registry were followed for incident AF. Those with likely pathogenic or pathogenic variants in sarcomeric genes were included. The AF incidence was ascertained by review of medical records and electrocardiograms at each investigative site. One thousand forty adult HCM patients, without baseline AF and with likely pathogenic or pathogenic variation in either MYH7 (n=296), MYBPC3 (n=659), or thin filament genes (n=85), were included. Compared with patients with variation in other sarcomeric genes, those with MYH7 variants were younger on first clinical encounter at the Sarcomeric Human Cardiomyopathy Registry site and more likely to be probands than the MYBPC3 variants. During an average follow-up of 7.2 years, 198 incident AF events occurred. Patients with likely pathogenic or pathogenic mutations in MYH7 had the highest incidence of AF after adjusting for age, sex, proband status, left atrial size, maximal wall thickness, and peak pressure gradient (hazard ratio, 1.7; 95% CI, 1.1–2.6; P=0.009).ConclusionsDuring a mean follow-up of 7.2 years, new-onset AF developed in 19% of HCM patients with sarcomeric mutations. Compared with other sarcomeric genes, patients with likely pathogenic or pathogenic variation in MYH7 had a higher rate of incident AF independent of clinical and echocardiographic factors.

BackgroundNumerous quality metrics for heart failure (HF) care now exist based on process and outcome. What remains unclear, however, is if the correct quality metrics are being emphasized. To determine the validity of certain measures, we compared correlations between measures and reliability over time. Measures assessed include guideline-recommended β-blocker (BB), any BB, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, mineralocorticoid receptor antagonist, and hydralazine/isosorbide dinitrate (in blacks) use among candidates, 30-day mortality, 1-year mortality, and 30-day readmission.Methods and ResultsThis was an observational cohort analysis using chart review and electronic resources for 55 735 patients from 102 Veterans Affairs medical centers hospitalized with HF from 2008 to 2013. Assessments of convergent validity and reliability were performed. Significant correlations were found between in-hospital rates of ACE inhibitor use and the following measures: BB use, 30-day mortality, and 1-year mortality. Guideline-recommended BB use was also significantly correlated with mineralocorticoid receptor antagonists, 30-day mortality, and 1-year mortality. There was no correlation between 30-day readmission rates and any therapy or mortality. Measure reliability over time was seen for guideline-recommended BBs (r=0.57), mineralocorticoid receptor antagonists (r=0.50), 30-day mortality (r=0.29), and 1-year mortality (r=0.31). ACE inhibitor and readmission rates were not reliable measures over time.ConclusionsBB use, ACE inhibitor use, mortality, and mineralocorticoid receptor antagonist use are valid measures of HF quality. Thirty-day readmission rate did not seem to be a valid measure of HF quality of care. If the goal is to identify high-quality HF care, the emphasis on decreasing readmission rates might be better directed towards improving usage of the recommended therapies.

Catheter ablation is a well-established treatment for atrial fibrillation. A subset of patients developed dyspnea secondary to loss of left atrial (LA) compliance after ablation, which is referred as the stiff LA syndrome.1 Stiff LA syndrome has traditionally been associated with profound eccentric LA remodeling. We report the case of a patient with this clinical syndrome who developed giant V waves during exercise but had a strikingly small LA.
A 76-year-old man who had been a competitive cyclist was referred for invasive hemodynamic exercise testing for evaluation of dyspnea, which had become progressively more severe during the past 3 years. Medical history was notable for chronic systemic hypertension and atrial fibrillation, which had been treated with 3 ablation procedures in the preceding 2 decades. ECG revealed normal sinus rhythm, and transthoracic echocardiography demonstrated normal left ventricular ejection fraction (57%), LA volume of 34 mL (indexed LA volume, 16 mL/m2; Figure), impaired LA reservoir function (LA ejection fraction, 27%), a structurally normal mitral valve with mild regurgitation, normal right ventricular systolic function, and an estimated right ventricular systolic pressure of 36 mm Hg. There was no evidence of pulmonary vein stenosis or pulmonary embolism on computed tomography.
Figure. Pulmonary capillary wedge pressure tracings and echocardiograms at rest and during peak exercise.A, Baseline 4-chamber echocardiogram showing a small left atrium. B, Pulmonary capillary wedge pressure waveforms at rest and (C) during peak exercise. D, Simultaneously obtained sonogram of the lung parenchyma shows development of B lines indicative of interstitial pulmonary congestion. E, Simultaneous echocardiography revealed only mild mitral regurgitation. LV indicates left ventricle. *Peak of the V wave.
Cardiac catheterization revealed mildly elevated right atrial pressure (8 mm Hg) and normal mean pulmonary artery pressure (19 mm Hg) at rest. Pulmonary artery wedge pressure was normal (14 mm Hg at mid C wave) with a prominent V wave (34 mm Hg; Figure). The patient exercised to exhaustion on a supine cycle ergometer achieving a peak workload of 120 W (peak Vo2, 15.7 mL/min per kg). Right atrial pressure (17 mm Hg) and mean pulmonary arterial pressure (43 mm Hg) increased during exercise. Pulmonary capillary wedge pressure increased to 38 mm Hg, with an increase in the V-wave amplitude to 72 mm Hg (Figure). The patient complained of severe dyspnea, and simultaneous echocardiographic imaging revealed development of sonographic lung B lines (12 lines over 4 left chest sites; Figure) but only mild mitral regurgitation with minimal change in LA volume from rest to peak exercise (31–32 mL). Based on the findings, the diagnosis of the stiff LA syndrome was made.
The stiff LA syndrome is an important complication that may develop years after surgical or catheter ablation.1 Ablation can prevent LA enlargement because of scarring, but in this case, the LA was exceedingly small, particularly in view of a long-standing history of atrial fibrillation. This suggests that the prior ablation procedures might have caused LA contracture. The normal LA dilates during exercise to augment reservoir function and receive greater venous return from pulmonary veins, protecting the lung capillaries from barotrauma. When the LA volume shrinks, as in this case, this ability to function as a compliance chamber that stores blood during ventricular systole is exhausted, leading to pulmonary venous hypertension with profound increase in the height of the V wave, even in the absence of mitral regurgitation.
LA dilation clearly promotes LA dysfunction, increased filling pressures, and worsening pulmonary hypertension and is an important treatment target.2 However, this case illustrates that some degree of LA dilation may also serve as an important compensatory mechanism to protect the lung capillaries from the hydrostatic trauma induced by LA hypertension. With LA contracture, atrial and thus pulmonary venous pressure increases dramatically as the atrium fills to the steeper portion of its compliance curve, leading to the development of so-called giant V waves even in the absence of mitral regurgitation (Figure). The subsequent increase in pulmonary capillary pressure then favors fluid filtration out of the vascular space and into the lung parenchyma, leading to the development of interstitial edema (B lines; Figure [D]) and the perception of dyspnea.3
Treatment remains unknown. Creation of an interatrial septostomy may be helpful to mitigate the pressure rise, as has been performed in patients with heart failure, as well as stiff LA syndrome.4,5 However, it is unknown whether the septal defect created through these approaches (8 mm) would be sufficient to allow normalization of LA pressure in a case such as this. Prevention may be the most effective treatment. Atrial ablations may reduce LA volume because of myocyte injury, fibrosis, and scar formation. Further study is required to devise less traumatic ablative procedures and to determine whether antifibrotic drugs, such as mineralocorticoid antagonists, may prevent or even reverse LA fibrosis.6
In summary, although LA reverse remodeling is a generally a favorable indicator that is associated with lower risk for atrial fibrillation recurrence and better outcomes, the current data suggest that LA volume contraction or failure to dilate could also contribute to pulmonary venous hypertension and symptomatic heart failure in some patients. Further study is needed to better understand the complex role of the LA in patients with cardiovascular disease.
Dr Borlaug has received research funding from the National Heart, Lung, and Blood Institute (RO1 HL128526, R01 HL126638, U01 HL125205, and U10 HL110262). Dr Obokata is supported by a research fellowship from the Uehara Memorial Foundation, Japan.
None.
https://www.ahajournals.org/journal/circheartfailure

Background: Coronary artery fluid dynamics may be altered because of the nonphysiological flow seen in continuous-flow left ventricular assist devices (CF-LVADs). Our aim was to study the structure and composition of coronary vessels after CF-LVAD.Methods and Results: Coronary arteries were collected from patients with heart failure (HF) at the time of transplantation, of whom 15 were supported with a CF-LVAD before transplant (HF+LVAD group) and 9 were not (HF non-LVAD group). In addition, coronary samples were obtained from 5 nonfailing age-matched donors (nonfailing group). Histological analysis was performed to quantify coronary morphology, composition, vascular fibrosis, and vasa vasorum density. The age and sex mix of the 3 groups were similar, and the mean duration of LVAD support was 213 days. Compared with patients with HF and nonfailing donors, the arteries from patients with HF+LVAD had expansion of the adventitia, breakdown of the internal elastic lamina, and increased adventitial collagen deposition and density of vasa vasorum.Conclusions: Among patients supported with CF-LVADs, the coronary arteries develop marked remodeling with increased adventitial fibrosis. The physiological consequences of these structural changes are unknown, but it is possible that arterial contractility may be impaired, thus limiting coronary flow reserve and promoting myocardial ischemia. This may contribute to CF-LVAD complications, such as ventricular arrhythmias and right ventricular failure. As more patients receive CF-LVADs and new pump technology attempts to modulate flow profiles and pulsatility, further research is needed to understand the mechanisms and long-term sequela of these changes in coronary arteries and other vascular beds.

Background: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest.Methods and Results: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP≥15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of “PCWP/CO slope” in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2±0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4±1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo2 (P<0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P=0.03) at a median 5.3-year follow-up.Conclusions: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis.

Background: The higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups.Methods and Results: In the WHI (Women’s Health Initiative; 1993–2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased (P<0.0001, interaction of race/ethnicity and RF number P=0.18)—African-Americans 1 RF: 1.80 (1.01–3.20), 2 RFs: 3.19 (1.84–5.54), 3+ RFs: 7.31 (4.26–12.56); Whites 1 RF: 1.27 (1.04–1.54), 2 RFs: 1.95 (1.60–2.36), 3+ RFs: 4.07 (3.36–4.93); Hispanics 1 RF: 1.72 (0.68–4.34), 2 RFs: 3.87 (1.60–9.37), 3+ RFs: 8.80 (3.62–21.42). Risk of death before developing HF increased with subsequent RFs (P<0.0001) but differed by racial/ethnic group (interaction P=0.001). The number of RFs was not associated with the risk of death after developing HF in any group (P=0.25; interaction P=0.48).Conclusions: Among diverse racial/ethnic groups, an increase in the number of baseline RFs was associated with higher risk of HF and death before HF but was not associated with death after HF. Early RF prevention may reduce the burden of HF across multiple racial/ethnic groups.

See Article by Saku et alMyocardial infarction (MI) and ischemic heart disease are leading causes of morbidity and mortality. Globally, 110 million people live with ischemic heart disease,1 and >8 million per year die secondary to ischemic heart disease.2 As for MI, the 2018 Heart and Disease Stroke Statistics update of the American Heart Association reported a prevalence of 7.9 million adults in the United States alone. In 2015, >110 000 patients died because of MI, with 30-day in-hospital mortality of 15%.3 Both of these conditions combine as the most common cause of heart failure (HF), either from chronic ischemia or from resultant injury after MI. Up to 40% of individuals with MI develop left ventricular (LV) dysfunction.4 The infarct size with resultant adverse ventricular remodeling is directly associated with the development of HF after MI.4 Cardiogenic shock, the worst expression of HF, in the setting of acute myocardial dysfunction is preceded by myocardial contractile dysfunction, which leads to inadequate tissue perfusion and, in turn, can result in multiorgan failure. Although the prevalence of cardiogenic shock among patients with MI is relatively low (5%–10%),5 cardiogenic shock has historically had an early mortality rate as high as 80%, whereas recent studies have suggested a decline in mortality to ≈40%,6 which is nevertheless still too high.Traditionally, coronary artery reperfusion using percutaneous intervention has been the cornerstone therapy to reduce myocardial damage and subsequent HF. Moreover, early percutaneous coronary intervention, using the latest generation of drug-eluted stents and novel antithrombotics and pharmacological therapies, has significantly reduced mortality in MI-related cardiogenic …

Background: To better understand reverse left ventricular (LV) remodeling, we developed a murine model wherein mice develop LV remodeling after transverse aortic constriction (TAC) and a small apical myocardial infarct (MI) and undergo reverse LV remodeling after removal of the aortic band.Methods and Results: Mice studied were subjected to sham (n=6) surgery or TAC+MI (n=12). Two weeks post-TAC+MI, 1 group underwent debanding (referred to as heart failure debanding [HF-DB] mice; n=6), whereas the aortic band remained in a second group (heart failure [HF] group; n=6). LV remodeling was evaluated by 2D echocardiography at 1 day, 2 weeks and 6 weeks post-TAC+MI. The hearts were analyzed by transcriptional profiling at 4 and 6 weeks and histologically at 6 weeks. Debanding normalized LV volumes, LV mass, and cardiac myocyte hypertrophy at 6 weeks in HF-DB mice, with no difference in myofibrillar collagen in the HF and HF-DB mice. LV ejection fraction and radial strain improved after debanding; however, both remained decreased in the HF-DB mice relative to sham and were not different from HF mice at 6 weeks. Hemodynamic unloading in the HF-DB mice was accompanied by a 35% normalization of the HF genes at 2 weeks and 80% of the HF genes at 4 weeks.Conclusions: Hemodynamic unloading of a pathophysiologically relevant mouse model of HF results in normalization of LV structure, incomplete recovery of LV function, and incomplete reversal of the HF transcriptional program. The HF-DB mouse model may provide novel insights into mechanisms of reverse LV remodeling.

Obstruction within the circuit of a left ventricular assist device (LVAD) is a challenging situation for clinicians to definitively diagnose and manage. Available diagnostic tools are limited in their ability to visualize large portions within the device and cannulas, often leading to uncertainty as to whether redo surgery is required or if there are feasible medical or percutaneous alternatives. Here, we report a case of LVAD outflow graft obstruction, which by computed tomographic angiography (CTA) appeared to be intramural thrombus, but by intravascular ultrasound (IVUS) was shown to be compression external to the graft.A 62-year-old female with a continuous flow LVAD (HeartMate II Abbott, IL) 5 years prior presented to the emergency department with frequent low-flow alarms and syncope. The patient’s post-LVAD course had been complicated by outflow graft infection 1 year after initial implantation, necessitating an outflow graft replacement. She had also experienced multiple bleeding events for which her warfarin therapeutic goal was lowered.In the preceding year, her LVAD flows had steadily declined from 4.5 to 5.0 L/min to 2.7 to 2.8 L/min with an increasing frequency of low-flow alarms not responsive to the intravenous fluid administration or changes in LVAD …

In the article by Jessup et al, “2017 ACC/AHA/HFSA/ISHLT/ACP Advanced Training Statement on Advanced Heart Failure and Transplant Cardiology (Revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 Clinical Competence Statement on Management of Patients With Advanced Heart Failure and Cardiac Transplant): A Report of the ACC Competency Management Committee,” which published ahead of print …

Sudden cardiac death (SCD) prevention in patients with newly diagnosed ventricular dysfunction or heart failure with reduced ejection fraction is an important clinical issue. A lack of strong evidence has led to uncertainty in medical decision making and variable clinical practice in the use of wearable cardioverter-defibrillators (WCDs). In this context, the results of VEST (Vest Prevention of Early Sudden Death Trial)1 at the American College of Cardiology Scientific Sessions on March 10, 2018, in Orlando, FL were highly anticipated. However, interpretations of the trial results have been presented that we find difficult to reconcile. We wish to call attention to what we think is the most rigorous interpretation of VEST: the primary results were negative.The WCD is designed for patients at risk of SCD who are not immediate candidates for implantable cardioverter-defibrillator (ICD) therapy. This is most commonly because of a new diagnosis of left ventricular dysfunction, often after acute myocardial infarction (MI).2 Although ICDs improve survival over years of treatment in appropriately selected patients, reductions in the first 40 days postinfarction have not been conclusively demonstrated.3,4 Despite this lack of evidence, the Food and Drug Administration approved the WCD for use in 2002, primarily because of the ability of this noninvasive technology to deliver appropriate shocks in laboratory settings and case series.5Although the WCD may seem benign—prompting a philosophy among some of why not, or better safe than sorry—there are reasons its efficacy and value should be …

Background: Continuous-flow left ventricular assist devices (CF-LVADs) have become a standard treatment choice in advanced heart failure patients. We hypothesized that practice patterns with regards to CF-LVAD utilization vary significantly among transplant centers and impact waitlist outcomes.Methods and Results: The United Network for Organ Sharing registry was queried to identify adult patients who were waitlisted for heart transplantation (HT) between 2008 and 2015. Each patient was assigned a propensity score based on likelihood of receiving a durable CF-LVAD before or while waitlisted. The primary outcomes of interest were death or delisting for worsening status and HT at 1 year. A total of 22 863 patients from 92 centers were identified. Among these, 9013 (39.4%) were mechanically supported. CF-LVAD utilization varied significantly between and within United Network for Organ Sharing regions. Freedom from waitlist death or delisting was significantly lower in propensity-score–matched patients who were mechanically supported versus medically managed (83.5% versus 79.2%; P<0.001). However, cumulative incidence of HT was also lower in mechanically supported patients (53.3% versus 63.6%; P<0.001). Congruous mechanical and medical bridging strategies based on clinical risk profile were associated with lower risk of death or delisting (hazard ratio, 0.88; P=0.027) and higher likelihood of HT (hazard ratio, 1.14; P<0.001).Conclusions: CF-LVAD utilization may lower waitlist mortality at the expense of lower likelihood of HT. Decision to use CF-LVAD and timing of transition should be individualized based on patient-, center-, and region-level risk factors to achieve optimal outcomes.

Background: In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients.Methods and Results: We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan (P<0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events (P interaction>0.90).Conclusions: Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension.

Background: As heart failure prevalence continues to increase in the setting of a static donor supply, left ventricular assist device (LVAD) therapy for end-stage heart failure continues to grow. Anecdotal evidence suggests that malalignment of the LVAD inflow cannula may increase thrombosis risk, but this effect has not been explored mechanistically or quantified statistically. Our objective is to elucidate the impact of surgical angulation of the inflow cannula on thrombogenicity.Methods and Results: Unsteady computational fluid dynamics is used in conjunction with computational modeling and virtual surgery to model flow through the left ventricle for 5 different inflow cannula angulations. We use a holistic approach to evaluate thrombogenicity: platelet-based (Lagrangian) metrics to evaluate the platelet mechanical environment, combined with flow-based (Eulerian) metrics to investigate intraventricular hemodynamics. The thrombogenic potential of each LVAD inflow cannula angulation is quantitatively evaluated based on platelet shear stress history and residence time. Intraventricular hemodynamics are strongly influenced by LVAD inflow cannula angulation. Platelet behavior indicates elevated thrombogenic potential for certain inflow cannula angles, potentially leading to platelet activation. Our analysis demonstrates that the optimal range of inflow angulation is within 0±7° of the left ventricular apical axis.Conclusions: Angulation of the inflow cannula >7° from the apical axis (axis connecting mitral valve and ventricular apex) leads to markedly unfavorable hemodynamics as determined by computational fluid dynamics. Computational hemodynamic simulations incorporating Lagrangian and Eulerian metrics are a powerful tool for studying optimization of LVAD implantation strategies, with the long-term potential of improving outcomes.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension.Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters.Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Background: Early ambulation (EA) is associated with improved outcomes for mechanically ventilated and stroke patients. Whether the same association exists for patients hospitalized with acute heart failure is unknown. We sought to determine whether EA among patients hospitalized with heart failure is associated with length of stay, discharge disposition, 30-day post discharge readmissions, and mortality.Methods and Results: The study population included 369 hospitals and 285 653 patients with heart failure enrolled in the Get With The Guidelines-Heart Failure registry. We used multivariate logistic regression with generalized estimating equations at the hospital level to identify predictors of EA and determine the association between EA and outcomes. Sixty-five percent of patients ambulated by day 2 of the hospital admission. Patient-level predictors of EA included younger age, male sex, and hospitalization outside of the Northeast (P<0.01 for all). Hospital size and academic status were not predictive. Hospital-level analysis revealed that those hospitals with EA rates in the top 25% were less likely to have a long length of stay (defined as >4 days) compared with those in the bottom 25% (odds ratio, 0.83; confidence interval, 0.73–0.94; P=0.004). Among a subgroup of fee-for-service Medicare beneficiaries, we found that hospitals in the highest quartile of rates of EA demonstrated a statistically significant 24% lower 30-day readmission rates (P<0.0001). Both end points demonstrated a dose–response association and statistically significant P for trend test.Conclusions: Multivariable-adjusted hospital-level analysis suggests an association between EA and both shorter length of stay and lower 30-day readmissions. Further prospective studies are needed to validate these findings.

Background: Peripartum cardiomyopathy (PPCM) is a rare disorder associated with pregnancy that can lead to life-threatening conditions. The incidence and clinical characteristics of this condition remain poorly understood.Methods and Results: We aimed to perform the first population-based study of PPCM in South Korea, using the Korea National Health Insurance Claims Database of the Health Insurance Review and Assessment Service. Patients who fulfilled predefined diagnostic criteria for PPCM from January 1, 2010, to December 31, 2012, were identified from International Classification of Diseases, Tenth Revision, Clinical Modification codes. To discriminate PPCM from other causes of heart failure, we excluded subjects who already had heart failure-related International Classification of Diseases, Tenth Revision, Clinical Modification codes at least 1 year before delivery. During the study period, there were 1 404 551 deliveries in South Korea, and we excluded 20 159 patients who already had heart failure. In those, a total of 795 cases were identified as PPCM. Patients with PPCM were older, had a higher prevalence of preeclampsia and gestational diabetes mellitus, and were more likely to be primiparous and have multiple pregnancies. Moreover, cesarean section and pregnancy-related complications and in-hospital death were also more common in patients with PPCM. Intriguingly, a considerable number of heart failure cases (n=64; 8.1% of total PPCM) were noted between 5 and 12 months after delivery.Conclusions: The incidence of PPCM was 1 in 1741 deliveries in South Korea. Patients with PPCM were older, were more associated with primiparity and multiple pregnancy, had more pregnancy-related complications, and revealed higher in-hospital mortality than controls. The number of cases diagnosed as PPCM were decreased over time after delivery; however, a large number of patients were still noted through 12 months after delivery.

See Article by S. Lee et alPregnancy-associated heart diseases substantially contribute to maternal morbidity and mortality. Among these, peripartum cardiomyopathy (PPCM), an idiopathic cardiomyopathy that causes heart failure with reduced left ventricular ejection fraction, represents one of the major life-threatening diseases in previously healthy women. The clinical course ranges from milder forms with slightly depressed left ventricular ejection fraction to severe forms with cardiogenic shock.1,2 Although greater awareness and understanding of PPCM have developed over recent years, major gaps remain about epidemiology, risk factors, pathophysiology, and targeted therapy. As such, the exact diagnosis of PPCM remains a fundamental challenge in both clinical practice and scientific analysis.In this issue of Circulation: Heart Failure, Lee et al3 present important data on the incidence and risk factors of PPCM in South Korea. The authors retrospectively analyzed a nationwide database that covers a total of 97% of the Korean population, hence expanding the knowledge of PPCM in Asian countries. The estimated incidence of PPCM in South Korea is 1:1741 (795 cases in 1 384 449 pregnancies; Figure). This compares well to the incidences reported in the United States and Germany but is markedly higher than those previously described in an analysis from Japan.4–6 The incidence of PPCM differs widely depending on the ethnic/racial and regional background of women. Interestingly, Africans and African Americans are at a higher risk for developing PPCM, with an estimated incidence of 1:100 in Nigeria and 1:299 in Haiti,1,3,7–9 whereas incidences in Caucasian populations range from 1:1000 in Germany to 1:10149 in Denmark.1,5,6,10 In a Japanese cohort, the incidence was as low as 1:20 00011; however, these results should be interpreted with caution because of methodological aspects, and …